tbuckley/cabot-search huggingface dataset:
RyR2 Serine-2030 PKA Site Governs Ca <sup>2+</sup> Release Termination and Ca <sup>2+</sup> Alternans
Authors: Jinhong Wei, Wenting Guo, Ruiwu Wang, John Paul Estillore, Darrell Belke, Yong-Xiang Chen, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, S.R. Wayne Chen
Journal: Circulation Research (2022)

PKA (protein kinase A)-mediated phosphorylation of cardiac RyR2 (ryanodine receptor 2) has been extensively studied for decades, but the physiological significance of PKA phosphorylation of RyR2 remains poorly understood. Recent determination of high-resolution 3-dimensional structure of RyR2 in complex with CaM (calmodulin) reveals that the major PKA phosphorylation site in RyR2, serine-2030 (S2030), is located within a structural pathway of CaM-dependent inactivation of RyR2. This novel structural insight points to a possible role of PKA phosphorylation of RyR2 in CaM-dependent inactivation of RyR2, which underlies the termination of Ca2+ release and induction of cardiac Ca2+ alternans.We performed single-cell endoplasmic reticulum Ca2+ imaging to assess the impact of S2030 mutations on Ca2+ release termination in human embryonic kidney 293 cells. Here we determined the role of the PKA site RyR2-S2030 in a physiological setting, we generated a novel mouse model harboring the S2030L mutation and carried out confocal Ca2+ imaging.We found that mutations, S2030D, S2030G, S2030L, S2030V, and S2030W reduced the endoplasmic reticulum luminal Ca2+ level at which Ca2+ release terminates (the termination threshold), whereas S2030P and S2030R increased the termination threshold. S2030A and S2030T had no significant impact on release termination. Furthermore, CaM-wild-type increased, whereas Ca2+ binding deficient CaM mutant (CaM-M [a loss-of-function CaM mutation with all 4 EF-hand motifs mutated]), PKA, and Ca2+/CaMKII (CaM-dependent protein kinase II) reduced the termination threshold. The S2030L mutation abolished the actions of CaM-wild-type, CaM-M, and PKA, but not CaMKII, in Ca2+ release termination. Moreover, we showed that isoproterenol and CaM-M suppressed pacing-induced Ca2+ alternans and accelerated Ca2+ transient recovery in intact working hearts, whereas CaM-wild-type exerted an opposite effect. The impact of isoproterenol was partially and fully reversed by the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide and the CaMKII inhibitor N-[2-[N-(4-chlorocinnamyl)-N-methylaminomethyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide individually and together, respectively. S2030L abolished the impact of CaM-wild-type, CaM-M, and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide-sensitive component, but not the N-[2-[N-(4-chlorocinnamyl)-N-methylaminomethyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide-sensitive component, of isoproterenol.
Orthogonal and complementary measurements of properties of drug products containing nanomaterials
Authors: C.G. Simon, S.E. Borgos, L. Calzolai, B.C. Nelson, J. Parot, E.J. Petersen, M. Roesslein, X. Xu, F. Caputo
Journal: Journal of Controlled Release (2023)

Quality control of pharmaceutical and biopharmaceutical products, and verification of their safety and efficacy, depends on reliable measurements of critical quality attributes (CQAs). The task becomes particularly challenging for drug products and vaccines containing nanomaterials, where multiple complex CQAs must be identified and monitored. To reduce (i) the risk of measurement bias and (ii) the uncertainty in decision-making during product development, the combination of orthogonal and complementary analytical techniques are generally recommended by regulators. However, despite frequent reference to “orthogonal” and “complementary” in guidance documents, neither term is clearly defined. How does one determine if two analytical methods are orthogonal or complementary to one another? Definitions are needed to design a robust characterization strategy aligned to regulatory needs. Definitions for “orthogonal” and “complementary” are proposed that are compatible with existing metrological terminology and are applicable to complex measurement problems. Orthogonal methods target the quantitative evaluation of the true value of a product attribute to address unknown bias or interference. Complementary measurements include a broader scope of methods that reinforce each other to support a common decision. Examples of the application of these terms are presented, with a focus on measurement of physical properties of nano-enabled drug products, including liposomes and polymeric nanoparticles for cancer treatment, lipid-based nanoparticles (LNPs) and virus-like particles for nucleic acid delivery. The proposed framework represents a first step in advancing the assessment of the orthogonality and complementarity of two measurements and it can potentially serve as the basis for a future international standard. This framework may help product developers to implement more efficient product characterization strategies, accelerate the introduction of novel medicines to the clinic and be applicable to other therapeutics beyond nanomaterial-containing pharmaceuticals.
Assessment of Mental Health Services Available Through Smartphone Apps
Authors: Erica Camacho, Asher Cohen, John Torous
Journal: JAMA Network Open (2022)

Importance As more patients and clinicians are turning to mental health smartphone apps to expand access to services, little is known about the current state of the app marketplaces and what these apps are actually offering in terms of features, privacy, price, and services. Objective To assess the current state of mental health apps, explore the association between app privacy scores and popularity as measured by star ratings and downloads, and to understand opportunities and challenges facing the commercial app landscape. Design, Setting, and Participants This cross-sectional study had trained raters using the public-facing M-Health Index and Navigation Database (MIND) to assess and review 578 mental health apps. The sample of apps used in this analysis were pulled from MIND and include apps across various conditions including schizophrenia, eating disorders, sleep, and more. Analysis of these apps was conducted in June 2022. Exposures There were 578 mental health apps rated across 105 dimensions derived from the American Psychiatric Association’s app evaluation framework. Main Outcomes and Measures App raters assessed each app across 6 categories: (1) app origin and accessibility, (2) privacy and security, (3) clinical foundation, (4) features and engagement, (5) inputs and outputs, and (6) interoperability. Privacy scores were determined by 5 MIND criteria, including (1) having a privacy policy, (2) reporting security measures in place, (3) declaring data use and purpose, (4) allowing for the deletion of data, and (5) allowing users to opt out of data collection. Correlations between privacy scores and popularity metrics (star ratings and number of downloads) were measured. Results This study included 578 mental health apps that were identified, assessed, and analyzed across 105 MIND dimensions. Psychoeducation, goal setting, and mindfulness were among the top app features. Of the 578 apps analyzed, 443 (77%) had a privacy policy. This analysis of apps with a privacy policy revealed that there was no statistically significant correlation between privacy scores and Apple App Store ( r = 0.058, P = .29) or Google Play Store star ratings ( r = 0.041; P = .48). The number of app downloads on the Google Play Store, however, was weakly correlated with privacy scores (χ 2 5 = 22.1; P &amp;amp;lt; .001). Conclusions and Relevance In this cross-sectional study of mental health apps, findings indicate that the current app marketplaces primarily offered basic features such as psychoeducation, goal tracking, and mindfulness but fewer innovative features such as biofeedback or specialized therapies. Privacy challenges remained common, and app popularity metrics provided little help in identifying apps with more privacy.
CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor
Authors: Nataliya Prokhnevska, Maria A. Cardenas, Rajesh M. Valanparambil, Ewelina Sobierajska, Benjamin G. Barwick, Caroline Jansen, Adriana Reyes Moon, Petra Gregorova, Luke delBalzo, Rachel Greenwald, Mehmet Asim Bilen, Mehrdad Alemozaffar, Shreyas Joshi, Cara Cimmino, Christian Larsen, Viraj Master, Martin Sanda, Haydn Kissick
Journal: Immunity (2022)
Intravascularly infused extracellular matrix as a biomaterial for targeting and treating inflamed tissues
Authors: Martin T. Spang, Ryan Middleton, Miranda Diaz, Jervaughn Hunter, Joshua Mesfin, Alison Banka, Holly Sullivan, Raymond Wang, Tori S. Lazerson, Saumya Bhatia, James Corbitt, Gavin D’Elia, Gerardo Sandoval-Gomez, Rebecca Kandell, Maria A. Vratsanos, Karthikeyan Gnanasekaran, Takayuki Kato, Sachiyo Igata, Colin Luo, Kent G. Osborn, Nathan C. Gianneschi, Omolola Eniola-Adefeso, Pedro Cabrales, Ester J. Kwon, Francisco Contijoch, Ryan R. Reeves, Anthony N. DeMaria, Karen L. Christman
Journal: Nature Biomedical Engineering (2022)
Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency
Authors: Shiqiao Ye, Cankun Wang, Zhaohui Xu, Hui Lin, Xiaoping Wan, Yang Yu, Subhodip Adhicary, Joe Z. Zhang, Yang Zhou, Chun Liu, Matthew Alonzo, Jianli Bi, Angelina Ramirez-Navarro, Isabelle Deschenes, Qin Ma, Vidu Garg, Joseph C. Wu, Ming-Tao Zhao
Journal: Circulation Research (2022)

NOTCH1 pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left heart syndrome, where the left ventricle is underdeveloped. It is unknown how NOTCH1 regulates human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which NOTCH1 pathogenic variants lead to ventricular hypoplasia in hypoplastic left heart syndrome remain elusive.CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 genome editing was utilized to delete NOTCH1 in human induced pluripotent stem cells. Cardiac differentiation was carried out by sequential modulation of WNT signaling, and NOTCH1 knockout and wild-type differentiating cells were collected at day 0, 2, 5, 10, 14, and 30 for single-cell RNA-seq.Human NOTCH1 knockout induced pluripotent stem cells are able to generate functional cardiomyocytes and endothelial cells, suggesting that NOTCH1 is not required for mesoderm differentiation and cardiovascular development in vitro. However, disruption of NOTCH1 blocks human ventricular-like cardiomyocyte differentiation but promotes atrial-like cardiomyocyte generation through shortening the action potential duration. NOTCH1 deficiency leads to defective proliferation of early human cardiomyocytes, and transcriptomic analysis indicates that pathways involved in cell cycle progression and mitosis are downregulated in NOTCH1 knockout cardiomyocytes. Single-cell transcriptomic analysis reveals abnormal cell lineage determination of cardiac mesoderm, which is manifested by the biased differentiation toward epicardial and second heart field progenitors at the expense of first heart field progenitors in NOTCH1 knockout cell populations.NOTCH1 is essential for human ventricular-like cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm and modulating cell cycle progression. Because first heart field progenitors primarily contribute to the left ventricle, we speculate that pathogenic NOTCH1 variants lead to biased differentiation of first heart field progenitors, blocked ventricular-like cardiomyocyte differentiation, and defective cardiomyocyte proliferation, which collaboratively contribute to left ventricular hypoplasia in hypoplastic left heart syndrome.
A Sense of Belonging
Authors: Anita Blanchard, Barbara Bowman, Valerie Jarrett, Debra Malina, William McDade
Journal: New England Journal of Medicine (2022)

This documentary video from the New England Journal of Medicine, featuring retired University of Chicago Associate Dean for Graduate Medical Education Anita Blanchard, M.D., reflects on the importance of diversity and mentorship. As a Black woman training in a field that was (and remains) predominantly White, she found a sense of belonging thanks to the unconditional support and encouragement she received from Black senior professor James Bowman, M.D., Ph.D. Watch as Dr. Blanchard shares the personal experiences and stories that inspire her to strive to increase the diversity of physicians and improve health and life in the surrounding, largely minoritized, community. This video is based on a Graphic Perspective by Dr. Blanchard (A Sense of Belonging, in the October 8, 2020, issue).
Patient Portals to Support Care Partner Engagement in Adolescent and Adult Populations
Authors: Kelly T. Gleason, Danielle Peereboom, Aleksandra Wec, Jennifer L. Wolff
Journal: JAMA Network Open (2022)

Importance Family and other unpaid care partners may bridge accessibility challenges in interacting with the patient portal, but the extent and nature of this involvement is not well understood. Objective To inform an emerging research agenda directed at more purposeful inclusion of care partners within the context of digital health equity by (1) quantifying care partners’ uptake and use of the patient portal in adolescent and adult patients, (2) identifying factors involving care partners’ portal use across domains of the System Engineering Initiative for Patient Safety model, and (3) assessing evidence of perceived or actual outcomes of care partners’ portal use. Evidence Review Following Arksey and O’Malley’s methodologic framework, a scoping review of manuscripts published February 1 and March 22, 2022, was conducted by hand and a systematic search of PubMed, PsycInfo, Embase, and Web of Science. The search yielded 278 articles; 125 were selected for full-text review and 41 were included. Findings Few adult patient portal accounts had 1 or more formally registered care partners (&amp;amp;lt;3% in 7 of 7 articles), but care partners commonly used the portal (8 of 13 contributing articles reported &amp;amp;gt;30% use). Care partners less often authored portal messages with their own identity credentials (&amp;amp;lt;3% of portal messages in 3 of 3 articles) than with patient credentials (20%-60% of portal messages in 3 of 5 articles). Facilitators of care partner portal use included markers of patient vulnerability (13 articles), care partner characteristics (15 articles; being female, family, and competent in health system navigation), and task-based factors pertaining to ease of information access and care coordination. Environmental (26 articles) and process factors (19 articles, eg, organizational portal registration procedures, protection of privacy, and functionality) were identified as influential to care partner portal use, but findings were nuanced and precluded reporting on effects. Care partner portal use was identified as contributing to both patient and care partner insight into patient health (9 articles), activation (7 articles), continuity of care (8 articles), and convenience (6 articles). Conclusions and Relevance In this scoping review, care partners were found to be infrequently registered for the patient portal and more often engaged in portal use with patient identity credentials. Formally registering care partners for the portal was identified as conferring potential benefits for patients, care partners, and care quality.
Accelerating developments in heart failure
Authors: Thomas Thum, Carolyn S P Lam
Journal: Cardiovascular Research (2022)

Heart failure remains a leading cause of morbidity and mortality globally.Within the last 5 years, many new developments have been seen in the area of heart failure, including completely new therapies, mechanistic insights, as well as novel strategies to phenotype and segment the condition.Ten reviews and two original articles provide an updated overview on specific new developments in the area of heart failure.
Hippocampal spatial representations exhibit a hyperbolic geometry that expands with experience
Authors: Huanqiu Zhang, P. Dylan Rich, Albert K. Lee, Tatyana O. Sharpee
Journal: Nature Neuroscience (2022)

Daily experience suggests that we perceive distances near us linearly. However, the actual geometry of spatial representation in the brain is unknown. Here we report that neurons in the CA1 region of rat hippocampus that mediate spatial perception represent space according to a non-linear hyperbolic geometry. This geometry uses an exponential scale and yields greater positional information than a linear scale. We found that the size of the representation matches the optimal predictions for the number of CA1 neurons. The representations also dynamically expanded proportional to the logarithm of time that the animal spent exploring the environment, in correspondence with the maximal mutual information that can be received. The dynamic changes tracked even small variations due to changes in the running speed of the animal. These results demonstrate how neural circuits achieve efficient representations using dynamic hyperbolic geometry.
Small molecule-mediated disruption of ribosome biogenesis synergizes with FGFR inhibitors to suppress glioma cell growth
Authors: Asimina Zisi, Dimitris C Kanellis, Simon Moussaud, Ida Karlsson, Helena Carén, Lars Bräutigam, Jiri Bartek, Mikael S Lindström
Journal: Neuro-Oncology (2022)

Abstract Background High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition. Methods Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA pol I transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and viability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects. Results BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with Fibroblast Growth Factor Receptor (FGFR) inhibitor (FGFRi) Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR–FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus. Conclusions This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
Survival in male breast cancer over the past 3 decades
Authors: José P Leone, Rachel A Freedman, Julieta Leone, Sara M Tolaney, Carlos T Vallejo, Bernardo A Leone, Eric P Winer, Nancy U Lin, Michael J Hassett
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Breast cancer mortality in women has declined statistically significantly over the past several years. In men, it is unclear whether survival has changed over time. We evaluated changes in breast cancer–specific survival (BCSS) and overall survival (OS) in male breast cancer over the past 3 decades. Methods We evaluated men diagnosed with breast cancer between 1988 and 2017, reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007, and 2008-2017. BCSS and OS were estimated by Kaplan-Meier, and differences between groups were compared by log-rank test. Multivariable Cox regression evaluated the independent association of year of diagnosis with BCSS and OS. All tests were 2-sided. Results We included 8481 men. Overall, BCSS at 5 years was 83.69%, 83.78%, and 84.41% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .86). There was no statistically significant difference in BCSS between the 3 groups within each stage of disease. Among all patients, OS at 5 years was 64.61%, 67.31%, and 69.05% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .01). In adjusted Cox models, each additional year of diagnosis had no statistically significant association with BCSS (hazard ratio = 1.00, 95% confidence interval = 0.99 to 1.01, P = .75), but there was statistically significant improvement in OS (hazard ratio = 0.99, 95% CI = 0.98 to 0.99, P = .009). Conclusions Over the past 3 decades, there has been no statistically significant improvement in BCSS in male breast cancer. Changes in OS over time are consistent with increasing life expectancy. Efforts to improve BCSS in male breast cancer are warranted.
A multi-omics integrative network map of maize
Authors: Linqian Han, Wanshun Zhong, Jia Qian, Minliang Jin, Peng Tian, Wanchao Zhu, Hongwei Zhang, Yonghao Sun, Jia-Wu Feng, Xiangguo Liu, Guo Chen, Babar Farid, Ruonan Li, Zimo Xiong, Zhihui Tian, Juan Li, Zi Luo, Dengxiang Du, Sijia Chen, Qixiao Jin, Jiaxin Li, Zhao Li, Yan Liang, Xiaomeng Jin, Yong Peng, Chang Zheng, Xinnan Ye, Yuejia Yin, Hong Chen, Weifu Li, Ling-Ling Chen, Qing Li, Jianbing Yan, Fang Yang, Lin Li
Journal: Nature Genetics (2022)
Small intestine and colon tissue-resident memory CD8+ T cells exhibit molecular heterogeneity and differential dependence on Eomes
Authors: Yun Hsuan Lin, Han G. Duong, Abigail E. Limary, Eleanor S. Kim, Paul Hsu, Shefali A. Patel, William H. Wong, Cynthia S. Indralingam, Yi Chia Liu, Priscilla Yao, Natalie R. Chiang, Sara A. Vandenburgh, Taylor R. Anderson, Jocelyn G. Olvera, Amir Ferry, Kennidy K. Takehara, Wenhao Jin, Matthew S. Tsai, Gene W. Yeo, Ananda W. Goldrath, John T. Chang
Journal: Immunity (2022)
Subconjunctival Hemorrhage in Leptospirosis
Authors: Emilie C Rijnink, Prataap K Chandie Shaw
Journal: New England Journal of Medicine (2022)

An 18-year-old man presented with fever, vomiting, and diarrhea after falling into a canal 3 weeks earlier. The examination was notable for scleral icterus and subconjunctival hemorrhage in both eyes.